Silver hexafluoroantimonate-catalyzed three-component [2+2+1]cycloadditions of allenoates, dual activated olefins, and isocyanides

Article abstract of DOI:10.1002/adsc.201000795

The intermolecular [2+2+1]multicomponent cycloadditions from readily available allenoates, dual activated olefins and isocyanides catalyzed by silver hexafluoroantimonate were studied. This protocol allowed the syntheses of highly functionalized five-membered carbocycles with exclusive regioselectivity and stereoselectivity in an efficient and atom-economical manner.

Full text of DOI:10.1002/adsc.201000795

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DOI: 10.1002/adsc.201000795
Silver Hexafluoroantimonate-Catalyzed Three-Component
[2+2+1]Cycloadditions of Allenoates, Dual Activated Olefins,
and Isocyanides
Jian Li,a,* Yuejin Liu,a Chunju Li,a and Xueshun Jiaa,b,*
a
Department of Chemistry, Shanghai University, Shanghai 200444, Peopleꢀs Republic of China
Fax : (+86)-21-6613-4594, phone: (+86)-21-6613-2408; e-mail: lijian@shu.edu.cn or xsjia@mail.shu.edu.cn
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese
b
Academy of Sciences, 345 Lingling Road, Shanghai 200032, Peopleꢀs Republic of China
Received: October 21, 2010; Revised: January 4, 2011; Published online: April 12, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000795.
Abstract: The intermolecular [2+2+1]multicom-
ponent cycloadditions from readily available allen-
ACHTUNGTRENNUNGoates, dual activated olefins and isocyanides cata-
lyzed by silver hexafluoroantimonate were studied.
This protocol allowed the syntheses of highly func-
tionalized five-membered carbocycles with exclu-
sive regioselectivity and stereoselectivity in an effi-
cient and atom-economical manner.
thereby providing access to functionalized five-mem-
bered carbo- and heterocycles.[5,6] Further application
of this annulation strategy to the total syntheses of
natural products and the development of their asym-
metric variants have also been well established.[7,8]
Generally, the in situ formation of a zwitterionic inter-
mediate stemed from the nucleophilic addition be-
tween allenoate and phosphine was believed to play a
key role in this process. Accordingly, we envisaged
that a novel cycloaddition route based on the above
[3+2]annulation could be accessed if isocyanide was
employed as nucleophile other than phosphine. Ac-
cording to our assumption, isocyanide-triggered nu-
cleophilic attack towards allenoate would essentially
lead to the generation of an analogous reactive inter-
ꢀ
Keywords: atom economy; carbocycles; C C bond
formation; cycloaddition; silver
In recent years, the development of new methods that mediate, which could experience further cyclization to
provide synthetic efficiency and atom economy has form five-membered carbocycles when electron-defi-
been an important goal of synthetic chemistry.[1] Mul- cient olefins were used as trapping agent (Scheme 1).
ticomponent reactions (MCRs) are good candidates
To probe the feasibility of the proposed transforma-
for this target as they embody many features of ideal tion, we selected benzyl isocyanide 1a, ethyl 2,3-buta-
synthesis such as atom and step economy, conver- dienoate 2a and phenylidenemalononitrile 3a as
gence and structural diversity.[2] Among the MCRs,
those with isocyanides (IMCRs) have attracted enor-
mous attention from organic chemists, and thus iso-
cyanides have proved themselves to be irreplaceable
building blocks in modern organic chemistry. From an
organic view of point, methods starting from isocya-
nides often have distinct advantages including en-
hanced convergence, inherent atom economy, and the
great variety of isocyanides readily available for use.[3]
As a continuation of our interest in new approaches
with atom economy,[4] herein we wish to report a
novel three-component cycloaddition from allenoates,
dual activated olefins, and isocyanides.
Recently, the phosphine-catalyzed [3+2]cycloaddi-
tion of allenoates with electron-deficient species such
as olefins and imines have been fully investigated, lation and suggested [2+2+1] cycloaddition.
Scheme 1. Representative phosphine-catalyzed [3+2]annu-
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Jian Li et al.
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Table 1. Optimization of the reaction conditions.[a]
Entry Catalyst
Temp. [oC] Time [h] Yield [%][b]
1
2
3
FeCl3
RuCl3·xH2O
AuCl3
90
90
120
48
48
48
24
8
24
45
–
22
67
[c]
4
HAuCl4·3H2O 90
5[d]
6
AgOTf
AgSbF6
AgSbF6
90
90
25
120
90
90
90
120
90
120
90
8
85
7
48
18
24
24
48
24
24
24
48
trace
56
8[e]
9
Cu
A
[c]
Cu
N
–
10
11
12
13
14
15
CuI
K2PtCl6
17
16
trace
12
Pd
N
BiCl3
InCl3
BF3·Et2O
23
[f]
–
[a]
Figure 1. Single crystal X-ray structure of 4p.
All reactions were carried out with 0.5 mmol of benzyl
isocyanide 1a, 0.6 mmol ethyl 2,3-butadienoate 2a, and
0.5 mmol phenylidenemalononitrile 3a in 5 mL toluene
in air.
Yields of product after silica gel chromatography.
No formation of desired product 4a was detected.
Tf=trifluoromethanesulfonyl.
this process. A variety of isocyanides 1, allenoates 2
and dual activated olefins 3 were examined under the
optimal conditions and the results are summarized in
Table 2. The present reactions proceeded readily to
give products 4 in most cases and all compounds were
[b]
[c]
[d]
[e]
[f]
TFA=trifluoroacetic acid.
In such cases, a very complex mixture was formed.
1
characterized by IR, H NMR, 13C NMR, and HR-
mass spectra (see the Supporting Information).[9]
Moreover, the structure of compound 4p was unam-
model substrates (Table 1). Upon treatment of a pre- biguously confirmed by a single crystal X-ray analysis
formed toluene solution of 1a, 2a, and 3a with a cata- (Figure 1).[10] The analysis also showed that only the
lytic amount of FeCl3, formation of the expected [2+ Z-isomer was isolated and no formation of E-isomers
2+1]adduct 4a was observed although the reaction was detected.
was quite sluggish together with poor yield (Table 1,
As shown in Table 2, the catalysis system was firstly
entry 1). Gratifyingly, product 4a was isolated in 45% applied to substituted alkenes 3 derived from aromat-
yield in the presence of 5 mol% RuCl3·xH2O with tol- ic aldehydes. To our delight, treatment of isocyanide
uene as solvent (Table 1, entry 2). With this encourag- 1a and allenoate 2a with a series of substituted aryli-
ing result, several coinage metals were tested as cata- denes 3 produced the corresponding adducts 4 in
lysts. Among these potential catalysts, silver salts dis- moderate to excellent yields with high levels of ste-
played excellent performance (Table 1, entries 5 and reoselectivity. Olefins having electron-rich (Table 2,
6), whereas the use of other metal salts gave 4a in low entries 2 and 3), and electron-deficient substituents
yields (Table 1, entries 3, 4 and 8–14). Further experi- (Table 2, entries 4–8) on the aryl ring all performed
mental data also showed that the present conversion well, furnishing products 4 with 52–95% yields. Other
was sensitive to the reaction temperature as well as substituted olefins were also tested with the less nu-
the catalyst. While the present annulation reacted cleophilic isocyanide 1b under modified conditions to
smoothly at 908C in the presence of 5 mol% AgSbF6, give the desired products 4 with moderate yields
only a trace amount of the desired product 4a was af- (Table 2, entries 9–11). Having established the scope
forded at room temperature (Table 1, entry 7). Finally, and limitations with structurally diverse olefins and
the use of 5 mol% AgSbF6 in toluene at 908C was isocyanides, we sought to briefly investigate the feasi-
identified as the best conditions in terms of practicali- bility of substituted allenoates 2. As can be seen from
ty, selectivity, and the yield of 4a.
Table 2, olefins with electron-donating and electron-
With the optimized reaction conditions in hand, we withdrawing groups (Table 2, entries 13–20) bonded
turned our attention to the scope and limitation of to the aromatic rings underwent similar conversion
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Silver Hexafluoroantimonate-Catalyzed Three-Component [2+2+1]Cycloadditions
Table 2. AgSbF6-catalyzed three-component [2+2+1] cycloaddition of allenoate 2, isocyanide 1, and dual activated olefin 3.
Entry
Substrate 1
R2
Ar
Temp. [oC]
Time [h]
Product
Yield [%][a]
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1c
1d
1d
1d
1d
1d
1d
1d
1b
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Ph
90
90
90
90
90
90
90
90
120
120
120
90
120
120
120
120
120
120
120
120
8
8
8
8
8
8
8
8
18
18
18
6
24
24
24
24
24
24
24
24
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
85
52
70
87
90
65
92
95
64
75
81
76
59
45
61
40
80
76
65
49
3-MeOC6H4
4-CH3C6H4
4-NO2C6H4
2-BrC6H4
3-BrC6H4
4-BrC6H4
2,4-Cl2C6H3
Ph
9
10
11
12
13
14
15
16
17
18
19
20
2-ClC6H4
2-BrC6H4
Ph
Ph
4-CH3C6H4
4-NO2C6H4
3-NO2C6H4
2-ClC6H4
2-BrC6H4
4-BrC6H4
Ph
4s
4t
[a]
Yields of product after silica gel chromatography.
with 2-substituted allenoate 2b (R2 =Me) to yield the pathway. While behaving as traditional “three-carbon-
desired products 4 with satisfactory yields. Overall, atom units” in the phosphine-catalyzed [3+2]cyclo-
this [2+2+1]cycloaddition pathway constructs three additon process, only the external double bond of the
new carbon-carbon single bonds and a five-membered allenic fragment was utilized to complete this [2+2+
carbocycle in one step. A particularly notable aspect 1]cyclization in our method.
is the regioselectivity manifested in this annulation
Scheme 2. Proposed mechanism for the formation of 4.
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Jian Li et al.
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ed olefin 3 (0.5 mmol) in 5 mL toluene. The stirred mixture
was heated and the process was monitored using TLC detec-
tion. After completion of the present reaction, the reaction
mixture was concentrated under vacuum. The residue was
purified by column chromatography on silica gel [silica:
200–300; eluant: petroleum ether/ethyl acetate or cyclohex-
ane/ethyl acetate] to afford the desired product 4.
Scheme 3. Unprecedented reaction of isocyanide 1 and ben-
zylidenemalonates 5.
Acknowledgements
We thank the National Natural Science Foundation of China
(21002061, 20872087, 20902057), the Key Laboratory of Syn-
thetic Chemistry of Natural Substances, Chinese Academy of
Sciences, Leading Academic Discipline Project of Shanghai
Municipal Education Commission (No: J50101), and the
Postgraduate Innovation Fund of Shanghai University for fi-
nancial support.
The mechanism of this three-component cycloaddi-
tion reaction has not been unequivocally established,
but one reasonable possibility is proposed to account
for the formation of five-membered carbocycle
(Scheme 2). The beginning of the cyclization involves
the formation of vinyl-cation resonance structure
A$B as shown in Scheme 2.[11] And we believe that
the AgSbF6 behaves as a s-Lewis acid in such a
case.[12] The nucleophilic attack between isocyanide 1
and the vinyl-cation B essentially leads to the forma-
tion of zwitterionic species, which exist as a reso-
nance-stablized intermediate C$D.[13] The intermedi-
ate experiences further Michael addition followed by
intramolecular annulation to yield the product 4.[14]
Reactions of substituted benzylidenemalonates 5
with allenoates and isocyanides were also tested. To
our surprise, only two-component adducts 6 were iso-
lated as major products in these runs without the for-
mation of three-component annulation adducts. As
shown in Scheme 3, products 6 were produced in
moderate yields by heating the mixture of 1 and 5.[15]
Studies on the reaction mechanism and broadening of
the scope are currently in progress in our laboratory.
In conclusion, we have described a novel three-
component [2+2+1]cycloaddition reaction to gener-
ate functionalized cyclopentanone derivatives from
simple and readily available starting materials. Al-
though many synthetic methods for the formation of
carbocycles are available, the present procedure pro-
vides a fast synthetic route to highly substituted cyclo-
pentanone ring in an efficient and atom-economical
manner. This protocol is also distinguished by its con-
venient experimental set-up and excellent regioselec-
tivity and stereoselectivity. Further extension of the
present strategy to the syntheses of other functional-
ized carbo- and heterocycles is also in progress in our
laboratory.
References
[1] B. M. Trost, Science 1991, 254, 1471–1477.
[2] a) Multicomponent Reactions, (Eds.: J. Zhu, H. Bien-
aymꢂ), Wiley-VCH, Weinheim, Germany, 2005; b) A.
Dçmling, Chem. Rev. 2006, 106, 17–89; c) B. B. Toure,
D. G. Hall, Chem. Rev. 2009, 109, 4439–4486; d) J. D.
Sunderhaus, S. F. Martin, Chem. Eur. J. 2009, 15, 1300–
1308; e) N. Isambert, R. Lavilla, Chem. Eur. J. 2008, 14,
8444–8454; f) B. Ganem, Acc. Chem. Res. 2009, 42,
463–472.
[3] For recent examples on isocyanide chemistry, see: a) N.
Kielland, F. Catti, D. Bello, N. Isambert, I. Soteras, F. J.
Luque, R. Lavilla, Chem. Eur. J. 2010, 16, 7904–7915;
b) H. Mihara, Y. Xu, N. E. Shepherd, S. Matsunaga, M.
Shibasaki, J. Am. Chem. Soc. 2009, 131, 8384–8385;
c) M. C. Pirrung, S. Ghorai, T. R. Ibarra-Rivera, J. Org.
Chem. 2009, 74, 4110–4117; d) F. Sha, X. Huang,
Angew. Chem. 2009, 121, 3510–3513; Angew. Chem.
Int. Ed. 2009, 48, 3458–3461; e) S.-X. Yue, M. X. Wang,
D.-X. Wang, G. Masson, Angew. Chem. 2009, 121,
6845–6849; Angew. Chem. Int. Ed. 2009, 48, 6717–
6721; f) A. Dos Santos, L. El Kaim, L. Grimaud, C.
Ronsseray, Chem. Commun. 2009, 3907–3909.
[4] a) J. Li, S. Y. Li, C. J. Li, Y. J. Liu, X. S. Jia, Adv. Synth.
Catal. 2010, 352, 336–340; b) Y. N. Zhao, J. Li, C. J. Li,
K. Yin, D. Y. Ye, X. S. Jia, Green Chem. 2010, 12,
1370–1372.
[5] For reviews on phosphine-catalyzed reactions, see:
a) X. Lu, C. Zhang, Z. Xu, Acc. Chem. Res. 2001, 34,
535–544; b) J. L. Methot, W. R. Roush, Adv. Synth.
Catal. 2004, 346, 1035–1050; c) L.-W. Ye, J. Zhou, Y.
Tang, Chem. Soc. Rev. 2008, 37, 1140–1152; d) B. J.
Cowen, S. J. Miller, Chem. Soc. Rev. 2009, 38, 3102–
3116; e) A. Marinetti, A. Voituriez, Synlett 2010, 174–
197.
Experimental Section
[6] For relevant examples, see: a) C. Zhang, X. Lu, J. Org.
Chem. 1995, 60, 2906–2908; b) S. Xu, L. Zhou, R. Ma,
H. Song, Z. He, Chem. Eur. J. 2009, 15, 8698–8702;
c) C. E. Henry, O. Kwon, Org. Lett. 2007, 9, 3069–
3072; d) T. Dudding, O. Kwon E. Mercier, Org. Lett.
General Procedure for the Formation of Product 4
Catalyst AgSbF6 (5 mol%) was added to a solution of isocy-
anide 1 (0.5 mmol), allenoate 2 (0.6 mmol) and dual activat-
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Silver Hexafluoroantimonate-Catalyzed Three-Component [2+2+1]Cycloadditions
2006, 8, 3643–3646; e) Y. Xia, Y. Liang, Y. Chen, M.
Wang, L. Jiao, F. Huang, S. Liu, Y. Li, Z.-X. Yu, J. Am.
Chem. Soc. 2007, 129, 3470–3471; f) D. J. Wallace,
R. L. Sidda, R. A. Reamer, J. Org. Chem. 2007, 72,
1051–1054; g) M. Sampath, T.-P. Loh, Chem. Commun.
2009, 1568–1570.
Angew. Chem. 2009, 121, 7368–7371; Angew. Chem.
Int. Ed. 2009, 48, 7232–7235; b) B. B. Snider, D. K.
Spindell, J. Org. Chem. 1980, 45, 5017–5020; c) B. B.
Snider, E. Ron, J. Org. Chem. 1986, 51, 3643–3652;
d) H. M. R. Hoffmann, Z. M. Ismail, A. Weber, Tetra-
hedron Lett. 1981, 22, 1953–1956.
[7] a) Y. Du, X. Lu, J. Org. Chem. 2003, 68, 6463–6465;
b) J.-C. Wang, M. J. Krische, Angew. Chem. 2003, 115,
6035–6037; Angew. Chem. Int. Ed. 2003, 42, 5855–
5857; c) T. Q. Pham, S. G. Pyne, B. W. Skelton, A. H.
White, J. Org. Chem. 2005, 70, 6369–6377.
[8] a) J. E. Wilson, G. C. Fu, Angew. Chem. 2006, 118,
1454–1457; Angew. Chem. Int. Ed. 2006, 45, 1426–
1429; b) B. J. Cowen, S. J. Miller, J. Am. Chem. Soc.
2007, 129, 10988–10989; c) Y.-Q. Fang, E. N. Jacobsen,
J. Am. Chem. Soc. 2008, 130, 5660–5661; d) H. Xiao,
Z. Chai, C.-W. Zheng, Y.-Q. Yang, W. Liu, J.-K. Zhang,
G. Zhao, Angew. Chem. 2010, 122, 4569–4572; Angew.
Chem. Int. Ed. 2010, 49, 4467–4470.
[9] For examples of analogous skeleton, see: J. Baluenga,
R. Vicente, L. A. Lꢃpez, M. Tomꢄs, J. Am. Chem. Soc.
2006, 128, 7050–7054.
[10] CCDC 784375 for compound 4p contains the supple-
mentary crystallographic data for this paper. These
data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
[12] a) J.-M. Weibel, A. Blanc, P. Pale, Chem. Rev. 2008,
108, 3149–3173; b) M. ꢅlvarez-Corral, M. MuÇoz-
Dorado, I. Rodrꢆguez-Garcꢆa, Chem. Rev. 2008, 108,
3174–3198.
[13] For analogous generation of a zwitterionic intermedi-
ate, please see the reported examples on phosphine-
catalyzed cycloaddition reactions.[5]
[14] For dipolar cycloaddition processes triggered by isocya-
nides and other species, see: a) V. Nair, A. T. Biju, K.
Mohanan, E. Suresh, Org. Lett. 2006, 8, 2213–2216;
b) V. Nair, R. S. Menon, A. R. Sreekanth, N. Abhilash,
A. T. Biji, Acc. Chem. Res. 2006, 39, 520–530; c) C.
Ma, H. Ding, Y. Zhang, M. Bian, Angew. Chem. 2006,
118, 7957–7961; Angew. Chem. Int. Ed. 2006, 45, 7793–
7797; d) H. Ding, Y. Zhang, M. Bian, W. Yao, C. Ma, J.
Org. Chem. 2008, 73, 578–584; e) V. Nair, R. S. Menon,
P. B. Beneesh, V. Sreekumar, S. Bindu, Org. Lett. 2004,
6, 767–769; f) V. Nair, V. Sreekumar, S. Bindu, E.
Suresh, Org. Lett. 2005, 7, 2297–2300; g) C. Ma, Y.
Yang, Org. Lett. 2005, 7, 1343–1345.
13
[15] For 1H NMR,
C NMR and HR-mass spectra of 6,
[11] For a related formation of a vinyl-cation in the pres-
ence of Lewis acids, see: a) J.-F. Zhao, T.-P. Loh,
please see the Supporting Information for details.
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